PD (MC) - Block 1 Flashcards
What aspects of a drug can cross the BBB?
- More lipophillic (uncharged)
- EXCEPTION: Zwitterions can cross BBB through amino acid transporters
Therefore molecules with an overall charge of 0 will cross the BBB!
What COMT metabolism?
What is MOA metabolism?
Can we cure PD?
No curative tx, only palliative/sx tx:
1. Increase synthesis of brain dopamine (DA)
1. Stimulate DA release from presynaptic sites
1. Direct stimulation of DA receptors
1. Decreasing reuptake of DA at presynaptic sites
1. Decreasing metabolism of DA or L-DOPA
Inspite of therapy, we’ll see progressive loss of function over time
Pathology of PD?
Loss of dopaminergic neurons in substantia nigra – normally inhibit output of GABAergic cells in corpus striatum
What is the most effective drug for PD sx? Why?
L-DOPA
* Can’t give DA because charged at physiological conditions -> can’t bross BBB
* But L-DOPA is less basic (pKa = 8.72) and can form zwitterion -> can cross BBB
* More potent/safe than giving racemic mixture
* Levodopa by AADC to Dopamine
L-DOPA
Interactions, ADR, Counseling
Interactions: competes with aa for absorption
* Vit B6
ADR: N/V, psychiatric disturbances, postural hypotension, dyskinesias
* Don’t give antiemetics cause is reduce l-dopa effects
Counseling: fluctuating motor responses (on-off phenomenon) within 5-15 yr
Carbidopa
MOA, PK
MOA: competitively inhibits L-DOPA metabolism
* Decreases tox of L-DOPA due to much lower doses -> less N/V
PK: Too polar to cross BBB -> doesn’t inhibit decarboxylase in brain
What are examples of L-DOPA/Cabidopa combos?
Sinemet: IR or CR
Rytary: ER
* Capsules with beads at release drug at different rates
* Reduces wearing off effect of levodopa
Inbrija
Indication
Levodopa inhalation powder
Indication: PRN is effects wear off between PO of carbidopa/levodopa
* Devices can’t be pre-loaded: need to unwrap and insert PRN
* Might be difficult for PD patients
Only add to regimen of carbidopa/levodopa
Duopa
Indication
Levodopa/Carbidopa Intestinal Gel
Indication: Continuously pumped into small intestine via small tube in stomach
* used for advanced PD
What are the excitatory dopamine types?
D1, D5
What are the inhibitory dopamine types?
D2, 3, 4
What are the dopamine agonists?
Ergot: Bromocriptine
Non-ergot: Pramipexole, ropinirole, rotigotine
How does DARA differ from L-DOPA?
- Longer DOA and less likely to induce on/off effects and dyskinesias
- Initial monotherapy
- Usually gradually increase doses based on response and tolerance
- Do not require functioning dopaminergic nerve terminals
- No metabolic conversion required
Not as effective as L-DOPA
ADR of DARA?
- N/V
- Raynauds
- Erythromelalgia
- postural hypotension, sedation, headache and psychiatric disturbances
- Minimize GI with meals
SAR of Dopamine receptor agonists?
- Need cationic amine to bind to Asp residue on DA receptor
- Needs trans confirmation
Apomorphine
Receptor, Bioavailability, Indication
Receptors: agonist for D1 and 2 R
F: Low, but Lipophilic enough to cross BBB though
* Short DOA, potent central emetic action
Indication: Treats unpredicatble, frequne motor fluctuations
* Off phase immobility as “rescue” agent
* Must be titrated – risk of severe orthostatic hypotension
PD med where you can give an antiemetic?
Apomorphine with trimethobenzamide (antiemetic)
Kynmobi
Indication, ADR
SL apomorphine film
Indication: PRN if med wears off
ADR: dry mouth, oral mucosal irritation and swelling and throat irritation
Bromocriptine
Receptors, Bioavalability, ADR
Receptors: Partial agonist at D2 and D3 dopamine receptors
Bioavailabiltiy: Bad with first-pass because its a peptide
ADR: Dose is build up 2-3 months to avoid ADRs
Rotigotine
Receptors, Bioavailability
Receptor: Agonist at D1, D2 and D3
F: Bad. Very heavy first-pass metabolism -> given as a transdermal patch
ADR: reaction at application site
Ropinirole
Brand, Receptor, Bioavailability
Receptor: agonist at D2
F: Bad. Heavy first-pass metabolism
* Primarily metabolized by CYP1A2 (induced by smoking)
Pramipexole
Brand, Receptors, Bioavailability
Mirapex, Mirapex ER
Receptor: agonist at D2, D3, and D4
F: Good
DA R agonists?
- Apomorphine
- Kynmobi
- Bromocriptine
- Rotigotine
- Ropinirole (Requip, Requip XL)
- Pramipexole (Mirapex, Mirapex ER)
DA receptor agonist that has the best bioavailability?
Pramipexole (Mirapex, Mirapex ER)
Describe the function of COMT inhibitors?
- Slow metabolism of L-DOPA and also DA, but not a monotherpay
- Increase area under curve + bioavailability of L-dopa without increasing peak plasma levels (minimizing fluctuations)
ADR of COMT inhibitors?
- Increased brain DA: N, dyskinesias, psychiatric disturbances
- Severe diarrhea
- urine discoloration (entacapone)
COMT inhibitors?
- Opicapone
- Tolcapone/Entacapone
Tolcapone/Entacapone
How do they differ?
Tolcapone: longer DOA due to more lipophilicity
* Acts on brain and periphery
* BBW: fatal fulminant hepatic failure (requires montioring every 2 weeks for a year)
Entaopone: shorter DOA, acts in periphery
Both need catechol and adjacent NO2 for activity
How does opicapone differ from other COMT inhibitors?
Long acting, peripherally selective
* Take QHS
* No food 1 hr before or after
Describe the function of MOA inhibitors?
- MOA metabolizes dopamine at the primary amine
- Irreversible inactivation -> can see effects for up to 2 weeks after stop taking drug
What are the issues of inhibiting a metabolizing enzyme?
- Effects other drugs
- Toxicity
MOAIs
Interactions, ADR
Interactions: Common
* Avoid foods that are high in tyramine (aged or fermented foods)
ADR: sleep disturbaces, confusion, N, DZ, orthostatic hypotension, hallucinations
Types of MOAIs?
- Selegiline
- Rasagiline
- Safinamide
Selegiline
MOA, Indication
MOA: MAO-B irreversible inhibitor
Indication: Slows progression, use early as monotherpay for neuroprotection and delayed L-dopa therapy
* also use later as adjunctive therapy with L-Dopa
Rasagiline
MOA, INdications
MOA: Selective irreversible inhibitor of MAO-B (due to acetylene)
Indications: Maintains function in early stage patients
* Imporvess overall motor sx
Safinamide
MOA, Indication
MOA: Selective reversible inhibitor – does not form covalent bond (based off od alanine)
* Blocks voltage-dependent Na and Ca channles and inhibits glutamate release
Indications: Imporves motor sx as add-on (decreases off time)
What are the neuroprotective agents?
What is the first therapy for PD tx?
Anticholinergics
How do anticholinergics play a part in PD tx? Indications
Dopaminergic depletion -> Cholinergic overactivity
Can be pre-dopaminergic therapy for tremor
nADR of anticholinergics?
ti
Nonselective:
* Blurred visionlu
* Dry mouth
* Tachycardia
* Urinary difficulty
* HA
* Delirium
* Constipation
* Hallucinations
Start low, go slow
SAR of anticholinergics?
Anticholinergics used for PD?
- Benztropine (Cogentin)/Trihexyphenidyl
- Amantadine
Benztropine (Cogentin)/Trihexyphenidyl
Structure
Similar to antihistamines -> sedative
Amantadine
MOA, Indication, ADR
MOA: Overactivity of thalamocortical excitatory glutamatergic input to motor cerebral cortex may cause dyskinesia + excess release of glutamate may cause “excitotoxicity”
* Binds to NMDA channel
* Release of DA and NE from intraneuronal storage sites and blocks reuptake of DA
* Lipophilic “cage-like” ring structure -> crosses BBB easily
Indication: Can enhance the effects of L-DOPA, maybe lower severity of dyskinesias
ADR: transient effects, Livedo reticularis, CNS
Describe the mechanism of adenosine receptor antagonists
A2A receptor concentrated in striatum:
* Colocalized with D2 receptor - antagonistic interaction
* Activation of receptors also stimulates release of acetylcholine in striatum
* Also reduces binding affinity of DA for D2 receptors – antagonists should block inhibitory effects of A2A
Types of adenosine receptor antagonists?
- Istradefylline
Istradefylline
MOA, Indications, ADR
MOA: Selective A2A antagonist
Indications: Add-on with levodopa/carbidopa
ADR: dyskinesias, dizziness, constipation, nausea, hallucinations, sleeplessness (relation to caffeine)
What are the manifestations of L-DOPA Dose Response Fluctuations?
- Mid-afternoon loss of drug benefit
- Loss of sleep benefit: early-morning akinesia or foot dystonia
- Regular “wearing off” every 4 hours at first, may shorten with time
- Frequent wearing off, off-on, unpredictable response (50% of patients within 5 years)
- Dyskinesia and/or dystonias
When would L-DOPE wear off?
Regular predictable decline within 2-4 hrs after last dose (motor fluctuation)
Factors that causes L-dopa doses to get shorter with worsening sx?
- Worsening of dx process
- Narrowing of therapeutic window
What is the off-on response?
Sudden and unpredicatble: hard to manage
* Delayed on or drug failure occurs late afternoon and often due to poor gastric emptying or absorption (check for high protein diet - competition)
What causes L-DOPA indused dyskinesia?
Excessive dopaminergic stimulation from increasingly higher levodopa doses
What are central causes of response fluctuations (PD)?
- Pultsatile delivery to striatal receptors
- Impaired storage capacity
- Alteration of DA receptors
What are peripheral causes (PK) of response fluctuations?
- Delayed gastric emptying
- Dietary protein
- Short t1/2
What are essential tremors?
Postural tremors from b1 receptor dysfunction affecting hands, head, voice, and legs
What are tx for ET?
Propanolol is commonly used
* Primidone
* Anticonvulsants: gabapentic, topiramate
* Benzodiazepines: alprazolam, clonazepam, diazepam
* Botulinum Toxin Type A (Botox)
Patients with ET do NOT respond to levodopa
What is primidone?
Barbiturate anticonvulsant that is metabolized into phenobarbital:
* more effective than beta-blockers
* Better tolerated
* Combo with propranolol
When would benzos be used for ET?
PRN for anxiety provoking situations but not good for long term use
Botox use for hand and head tremors?
Hand: Reduced tremor amplitude by 30% but causes finger weakness
Head: Minimal side effects (better than hand)
